scholarly journals Restoring the Balance between Pro-Inflammatory and Anti-Inflammatory Cytokines in the Treatment of Rheumatoid Arthritis: New Insights from Animal Models

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 44
Author(s):  
Adrienn Markovics ◽  
Ken S. Rosenthal ◽  
Katalin Mikecz ◽  
Roy E. Carambula ◽  
Jason C. Ciemielewski ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune System ◽  
Animal Models ◽  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Memory Cell ◽  
Receptor Activation ◽  
Janus Kinase ◽  
Therapeutic Vaccines

Rheumatoid arthritis (RA) and other autoimmune inflammatory diseases are examples of imbalances within the immune system (disrupted homeostasis) that arise from the effects of an accumulation of environmental and habitual insults over a lifetime, combined with genetic predispositions. This review compares current immunotherapies—(1) disease-modifying anti-rheumatic drugs (DMARDs) and (2) Janus kinase (JAK) inhibitors (jakinibs)—to a newer approach—(3) therapeutic vaccines (using the LEAPS vaccine approach). The Ligand Epitope Antigen Presentation System (LEAPS) therapies are capable of inhibiting ongoing disease progression in animal models. Whereas DMARDs ablate or inhibit specific proinflammatory cytokines or cells and jakinibs inhibit the receptor activation cascade for expression of proinflammatory cytokines, the LEAPS therapeutic vaccines specifically modulate the ongoing antigen-specific, disease-driving, proinflammatory T memory cell responses. This decreases disease presentation and changes the cytokine conversation to decrease the expression of inflammatory cytokines (IL-17, IL-1(α or β), IL-6, IFN-γ, TNF-α) while increasing the expression of regulatory cytokines (IL-4, IL-10, TGF-β). This review refocuses the purpose of therapy for RA towards rebalancing the immune system rather than compromising specific components to stop disease. This review is intended to be thought provoking and look forward towards new therapeutic modalities rather than present a final definitive report.

scholarly journals Plasma levels of melatonin, certain cytokines and placental growth factor at non-pharmacological correction of pineal function in pregnant women with intrauterine growth restriction

2020 ◽  
Vol 8 (2) ◽  
Author(s):  
A. Berbets ◽  
Keyword(s):  
Immune System ◽  
Growth Factor ◽  
Pineal Gland ◽  
Pregnant Women ◽  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Placental Growth Factor ◽  
Placental Insufficiency ◽  
Tnf Α ◽  
Anti Inflammatory

The pineal gland produces the important hormone melatonin, the level of which in the blood of pregnant women decreases in case of placental insufficiency. The effect of dysfunction of the pineal gland on the immune system of pregnant women and on the angiogenic activity of the placenta during pregnancy remains insufficiently studied. Objective: to establish the effect of our method of non-drug correction of function of pineal gland on the state of the cytokine part of the immune system and on the synthesis of placental growth factor (PlGF) in pregnant women with placental insufficiency manifesting as fetal intrauterine growth restriction (IUGR). Material and methods. 46 pregnant women with IUGR at 30-36 weeks of gestation were examined. The group was divided into two subgroups: with non-drug correction of the pineal gland function (n = 25) and without correction (n = 21). The method of correction included a set of measures of following of lighting regimen, activity and sleep for 14 days. The control group consisted of 20 women with uncomplicated pregnancy. Levels of melatonin, PlGF, TNF-α, IL-1β, IL-6, IL-4, IL-10 were determined in the venous blood by enzyme-linked immunosorbent assay. Results. It was established that the concentration of melatonin in the blood of pregnant women with IUGR was significantly reduced, as well as the concentration of PlGF (p < 0.01). Significant changes were also found in pregnant women with placental insufficiency, namely, increased concentrations of proinflammatory cytokines, such as TNF-α (p < 0.05), IL-1-β (p < 0.001) and IL-6 (p < 0.05), comparing to healthy pregnant women. Also, in the group of pregnant women with IUGR the levels of anti-inflammatory cytokines IL-4 (p <0.001) and IL-10 (p < 0.001) were elevated in comparison to the control group. After application of the developed complex of non-drug correction of pineal gland function, the concentration of melatonin in the blood of pregnant women in the subgroup of correction increased significantly, comparing to the subgroup without correction (p < 0.001), as well as the level of PlGF (p < 0.05). Also, significantly lower levels of proinflammatory cytokines TNF-α, IL-1-β and IL-6 were observed in pregnant women in the subgroup of correction (p < 0.01). Regarding anti-inflammatory cytokines, under the influence of the developed complex of measures there was a decrease in the level of IL-4 and an increase in the level of IL-10 (p < 0.01). Conclusions. When the measures, aimed at non-drug correction of function of pineal gland, are applied in pregnant women with placental insufficiency, manifested as IUGR, the following changes are observed: increased of plasma levels of melatonin and placental growth factor, decreased of levels of proinflammatory cytokines. We suggest that the pineal gland exerts its effect on the immune system through melatonin, which moderates the activity of pro- and anti-inflammatory cytokines, thereby reducing the influence of inflammation on placental tissue, what results in increasing of concentrations of placental growth factor in the blood of pregnant women.

scholarly journals Are Janus Kinase Inhibitors Superior over Classic Biologic Agents in RA Patients?

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Przemyslaw J. Kotyla
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune System ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Cell Metabolism ◽  
Theoretical Background ◽  
Janus Kinase ◽  
Biologically Active ◽  
System Functioning ◽  
And Function

The Janus Kinases (JAKs) are a family of intracellular tyrosine kinases that provide transmission signals from cytokine, interferons, and many hormones receptors to the nucleus resulting in synthesis of many biologically active compounds and changing cell metabolism and function. That was theoretical background to synthetize the JAK inhibitors (Jakinibs). In recent years a substantial battery of evidence has been collected indicating the potential role of Jakinibs to interact with the specific elements of the immune system, therefore changing the inflammatory response. JAK kinase blockade offers a unique opportunity to block most of the key cytokines enabling the deep interaction into immune system functioning. Following discovery first Jakinibs were intensively studied in various forms of autoimmune diseases, including rheumatoid arthritis, and finally two Jakinibs tofacitinib and Baricitinib have been approved for the treatment of rheumatoid arthritis. Some clinical data indicated that under special circumstances Jakinibs may be even superior to biologics in the treatment of RA; however this suggestion should be verified in large clinical and observational studies.

scholarly journals Mechanisms of innate immunity in pathogenesis of psoriasis: approaches to targeted therapy

2020 ◽  
Vol 22 (3) ◽  
pp. 449-458
Author(s):  
E. D. Merkushova ◽  
E. M. Khasanova ◽  
L. V. Gankovskaya
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Targeted Therapy ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Pathological Process ◽  
Climatic Conditions ◽  
Keratinocyte Differentiation

Psoriasis is a chronic auto-inflammatory, genetically determined dermatosis, being multifactorial by origin, characterized by hyperproliferation of epidermis, affected keratinocyte differentiation and inflammatory reaction in dermis. The disease is characterized by a tendency to spread over the area of lesion, and involvement of articular tissue in the pathological process, which significantly affects the living standards of patients and causes their disability. There are many provoking factors that contribute to occurrence of psoriasis, or progression of existing psoriatic process in individuals with a genetic predisposition. These factors include adverse climatic conditions, skin trauma, exposure to ultraviolet light, burns, infections, etc.This review describes the role of innate immunity in pathogenesis of psoriasis, and describes in detail the mechanisms involved into induction of inflammation of PAMPs and DAMPs. In psoriasis, positively charged catelicidin is considered one of the most important DAMPs, which can form a complex with negatively charged cell polyanions-LL-37/auto-RNA and LL-37/auto-DNA. The interaction of PAMP/DAMP ligands with specific PRR receptors leads to signal activation of effector components of immune system, i.e., assembly of inflammasome complex, caspase activation, synthesis of inflammatory cytokines and processing of their immature forms. The review focuses on the role of TLRs under the conditions of physiological norm, which recognize danger signals and provide protection from pathogens and their timely elimination, and in development of pathological process. Activation of TLRs induces the production of pro-inflammatory cytokines, interferons and antimicrobial peptides, chemokines that support the development of psoriatic inflammation.In addition to TLRs, the mechanisms of involvement of inflammasomes in the development of psoriasis, which provides processing of mature forms of IL-1β and IL-18, are described in detail. Mature forms of these cytokines mediate the development of inflammation in psoriatic focus. In addition, processing of these cytokines by caspases using the positive feedback mechanism provides an additional signal to activate transcriptional activity of their genes and contributes to perpetuated inflammation.The review presents data confirming participation of inflammasomes in the pathogenesis of psoriasis. Much attention is paid to description of pharmacological inhibitors of inflammasomes, which in the future may be the drugs of choice for treatment of inflammatory diseases. The study of molecular mechanisms of the innate immune system will reveal new approaches to prognosis and development of targeted therapy for psoriasis.

scholarly journals Midkine in Inflammation

2011 ◽  
Vol 11 ◽  
pp. 2491-2505 ◽  
Author(s):  
Ludwig T. Weckbach ◽  
Takashi Muramatsu ◽  
Barbara Walzog
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Animal Models ◽  
Regulatory T Cells ◽  
Proinflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Autoimmune Encephalitis ◽  
Heparin Binding ◽  
Inflammatory Processes

The 13 kDa heparin-binding growth factor midkine (MK) was originally identified as a molecule involved in the orchestration of embryonic development. Recent studies provided evidence for a new role of MK in acute and chronic inflammatory processes. Accordingly, several inflammatory diseases including nephritis, arthritis, atherosclerosis, colitis, and autoimmune encephalitis have been shown to be alleviated in the absence of MK in animal models. Reduced leukocyte recruitment to the sites of inflammation was found to be one important mechanism attenuating chronic inflammation when MK was absent. Furthermore, MK was found to modulate expression of proinflammatory cytokines and the expansion of regulatory T-cells. Here, we review the current understanding of the role of MK in different inflammatory disorders and summarize the knowledge of MK biology.

Novel irreversible caspase-1 inhibitor attenuates the maturation of intracellular interleukin-1β

2007 ◽  
Vol 85 (1) ◽  
pp. 56-65 ◽  
Author(s):  
Xue-Qin Ma ◽  
Hua-Jie Zhang ◽  
Ya-Hui Zhang ◽  
Yi-Hua Chen ◽  
Fang Wu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokines ◽  
Caspase 3 ◽  
Inflammatory Diseases ◽  
Interleukin 1Β ◽  
Interleukin 18 ◽  
Caspase 1

. Caspase-1, the most efficient enzyme in processing the proinflammatory cytokines interleukin 1β and interleukin 18 in humans, is associated with inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and some neuronal diseases. We previously reported that isoquinoline-1,3,4-trione and its derivatives are novel caspase-3 inhibitors that could attenuate apoptosis in vitro and in vivo. Here we report a novel derivative of isoquinoline-1,3,4-trione that is highly potent in inhibiting caspase-1 activity in an irreversible and slow-binding manner, thus inhibiting cellular caspase-1 activity and the maturation of interleukin 1β in U-937 cells.

scholarly journals EFFICIANCY OF IMMUNOTHERAPY IN PATIENTS WITH PERSISTENT ALLERGIC RHINITIS

2018 ◽  
Vol 1 (70) ◽  
pp. 32-37
Author(s):  
Марина Антонюк ◽  
Marina Antonyuk ◽  
С Сулейманов ◽  
S Suleymanov ◽  
Татьяна Гвозденко ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Immune System ◽  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Specific Immunotherapy ◽  
Low Doses ◽  
Allergen Specific Immunotherapy ◽  
Specific Diagnosis ◽  
Persistent Allergic Rhinitis ◽  
Effect Of Treatment

The dynamics of parameters of cytokine status in patients with allergic rhinitis in view of efficiency of allergen-specific immunotherapy (ASIT) was studied in this work. 62 subjects with moderate persistent rhinitis at the age of 18-40 years old were included in the study. For specific diagnosis and treatment there we used standard allergens. ASIT was performed by the classical scheme. The concentrations of IL-4, IL-5, IL-6, IL-8 in the blood serum were measured by the enzyme immunoassay. A good or excellent effect of treatment with ASIT was achieved in 62.9% of cases, and satisfactory one in 37.1% of cases. The analysis of the dynamics of IL-4, IL-5, IL-6, IL-8 concentrations showed that the efficiency of ASIT in patients with allergic rhinitis depends on the ability of the immune system to activation by low doses of the allergen, quite fast suppression of proinflammatory cytokines induced by them, and active functioning of the system of anti-inflammatory cytokines.

scholarly journals P525 Rheumatoid arthritis treatment with filgotinib: Week 156 safety and efficacy data from a phase 2b open-label extension study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S452-S452
Author(s):  
R Besuyen ◽  
A Kavanaugh ◽  
R Westhovens ◽  
K Winthrop ◽  
S Lee ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Inflammatory Diseases ◽  
Day Treatment ◽  
Janus Kinase ◽  
Open Label ◽  
Safety And Efficacy ◽  
Open Label Extension ◽  
Grade 3

Abstract Background Filgotinib (FIL) is an oral, selective Janus kinase inhibitor, shown to be effective and well tolerated in patients (pt) with rheumatoid arthritis (RA) and other inflammatory diseases (IBD/AS/PsA). DARWIN 3, an ongoing, open-label, long-term extension of phase 2b studies evaluates the longer-term safety and efficacy of FIL in RA. Methods The study evaluated pt outcomes for methotrexate (MTX) inadequate responders completing the 24-week DARWIN 1 (FIL+MTX) and DARWIN 2 (FIL monotherapy) studies. We present an interim analysis at week 156 following FIL 200 or 100 mg/day treatment. Event rate: total events/total years of exposure of FIL; Exposure: until data cut-off in patients on the study at the time of analysis. Results Eight hundred and seventy-seven patients completed the parent studies. Seven hundred and thirty-nine enrolled in DARWIN 3 (497 DARWIN 1, 242 DARWIN 2); most DARWIN 1 and 2 patients were female (81.5%, 81.8%), white (75.3%, 74.8%); mean age was 53 and 52 years, respectively. Mean baseline MTX dose in the FIL+MTX group: 16.8mg/week. At week 156, 59.9% of patients remained on study. Most common reasons for discontinuation were adverse events (26.5%) and subject request (9.1%). Total exposure to FIL was 2203 pt-years; mean exposure ± standard deviation (SD): 3.04 ± 1.22 years for FIL+MTX and 2.86 ± 1.21 years for FIL monotherapy. Treatment-emergent adverse events (TEAEs): 419 (84.3%) patients on FIL+MTX and 203 (83.9%) patients on FIL monotherapy; serious TEAEs occurred in 45 (9.1%) and 33 (13.6%), respectively. Adverse event of special interest (AESI) rates remained low at week 156 (Table 1). Grade ≥3 toxicities in &gt;1% of patients were decreased lymphocytes (4.2%/1%), decreased neutrophils (1.0/1.2%), increased fasting triglycerides (2.2/0%) and decreased fasting triglycerides (0/3.3%) for FIL+MTX/FIL monotherapy respectively. 5 deaths occurred (FIL+MTX: 2, FIL monotherapy: 3) none after week 132. Clinical efficacy was shown at week 156 in both FIL+MTX and FIL monotherapy groups, using observed cases as measured by ACR20 (87.2% and 89.7%)/ACR50 (72.4 and 63.0)/ACR70 (45.5 and 40.0) DAS28(CRP) ≤3.2 (69.0 and 64.7) and DAS28(CRP) &lt;2.6 (53.4 and 45.6). Conclusion FIL was generally well tolerated; no new safety signals emerged. No safety differences observed in patients receiving FIL+MTX or FIL monotherapy. Efficacy was sustained up to week 156 in both treatment groups.

scholarly journals Secretion of proinflammatory cytokines by normal human melanocytes in response to lipopolysaccharide.

2011 ◽  
Vol 58 (4) ◽  
Author(s):  
Irena Tam ◽  
Krystyna Stępień
Keyword(s):  
Immune System ◽  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Large Body ◽  
Dependent Manner ◽  
Skin Immune System ◽  
Human Melanocytes ◽  
Tnf Α ◽  
Normal Human ◽  
Dose Dependent

A large body of evidence suggests that epidermal melanocytes are an integral part of the skin immune system and can be considered immunocompetent cells. Recently, it has been reported that human melanocytes constitutively express Toll-like receptors and may be involved in the induction of several inflammatory cytokines. In the study the secretion of IL-1β, IL-6 and TNF-α by cultured normal melanocytes was investigated after stimulation with lipopolysaccharide. LPS increased the secretion of IL-1β in a dose-dependent manner. IL-1β stimulated release of IL-6 and TNF-α by melanocytes, whereas LPS activated production of TNF-α, but not of IL-6. These observations indicate that LPS can participate in the regulation of cytokine activity in normal human melanocytes and suggest that cytokines released by melanocytes could affect melanocytes themselves or/and other cells of the epidermis.

Sign in / Sign up

Export Citation Format

Share Document